Thesis for the degree of Candidatus Pharmaciae APPLICATION ... · methods of organic chemistry limits chemists productivity a lot. A way to solve this problem is to do multiple reactions

Thesis for the degree of Candidatus Pharmaciae

APPLICATION OF ONE-POT SYNTHESIS OF Cu(I)-CATALYZED CYCLOADDITION BETWEEN AZIDES AND

TERMINAL ALKYNES: A NEW ONE-POT SYNTHESIS OF 1.4-DISUBSTITUTED 1,2,3-TRIAZOLES FROM TERMINAL ACETYLENES AND IN SITU

GENERATED AZIDES

Edmund André Høydahl

SECTION OF MEDICINAL CHEMISTRY DEPARTMENT OF PHARMACEUTICAL CHEMISTRY

SCHOOL OF PHARMACY UNIVERSITY OF OSLO

December 2006

ACKNOWLEDGEMENTS

I would like to thank Trond Vidar Hansen for the opportunity to work with an exciting

and new field in chemistry. I appreciated your competent guidance whenever it was

needed. It was always accompanied by a humorous tone.

Thanks to Kristin Odlo for helping me with practical things in the laboratory and other

things. I would never have found my way around the place without your help.

Thanks to the other staff at the Section of Medicinal Chemistry for helping me with

various instruments and so forth.

I would also like to say that I have appreciated the help from the other students at the

Section of Medicinal Chemistry with some of the many small problems faced when

writing this thesis.

Thanks to Silje Røysland for letting me benefit from her skills in the field of technology.

To Solveig: thank you for always being so kind to me.

Oslo, December 6, 2006

Edmund André Høydahl

The experiments in this master thesis have been performed at Section of Medicinal

Chemistry, Department of Pharmaceutical Chemistry, School of Pharmacy, University of

Oslo.

Supervisor: 1. Amanuensis Trond Vidar Hansen

School of Pharmacy, University of Oslo

2

Abstract

Multi-component reactions are a very elegant and rapid way to access highly functional

molecules from simple building blocks in drug lead synthesis. Multi-component one-pot

reactions generally afford good yields which is important in combinatorial synthesis.

Over the past decade, several sequential multi-component reactions have been developed

into multi-component one-pot reactions. Since multi-component one-pot reactions results

in a reduced number of operations, they usually allows direct transformation of

intermediates to desired products by avoiding isolation, handling and chromatography.

Hence, better yields are usually achieved.

In this study 1,4-disubstituted 1,2,3-triazoles were obtained by a high-yielding copper (I)

catalyzed 1,3-dipolar cycloaddition reaction between in situ generated azides and

terminal acetylenes. This one-pot, two-step procedure tolerated most functional groups

and circumvented the problems associated with the isolation of potentially toxic and

explosive organic azides. All of these factors are important in combinatorial synthesis of

drug lead compounds.

3

Abbreviations

13C NMR Carbon nuclear magnetic resonance

CDCl3 Deuterated chloroform

DMSO Deuterated methylsulfoxid

EtOAc Ethylacetate

EtOH Ethanol

GTP Guanosine 5-triphosphate

H Hydrogen 1H NMR Hydrogen nuclear resonance

HRMS High resolution mass spectrometry

HTS High throughput screening

Hz Hertz

J Coupling constant

MeOH Methanol

Mp Meltingpoint

[M+] Molecular ion

NaAscorbate Sodium ascorbate

PABA Para-aminobenzoic acid

Rf Retention factor

t-BuOH tert-buthanol

TLC Thin layer chromatography

α Alfa

β Beta

d Doublet

q Quartet

s Singlet

t Triplet

4

Table of contents ACKNOWLEDGEMENTS................................................................................................ 2 Abstract ............................................................................................................................... 3 Abbreviations...................................................................................................................... 4 Table of contents................................................................................................................. 5 1. Drug development........................................................................................................... 6

1.1 Introduction............................................................................................................... 6 1.2 Combinatorial chemistry:.......................................................................................... 7 1.3 High throughput screening........................................................................................ 9 1.4 Click chemistry ....................................................................................................... 10 1.5 Synthesis of starting compounds ............................................................................ 15 1.6 Tubulin and tubulin inhibitors ................................................................................ 18 1.7 Sulfonamides........................................................................................................... 20 1.8 Aim of study ........................................................................................................... 22

2. Results and Discussion ................................................................................................. 23 2.1 Syntheses................................................................................................................. 23

2.1.1 Syntheses of alkynes ........................................................................................ 23 2.1.2 Syntheses of azides. ......................................................................................... 30 2.1.3 Desalting of 3-(bromomethyl-)pyridine hydrobromide ................................... 32 2.1.4 Syntheses of bromides ..................................................................................... 33

2.2 Click reactions ........................................................................................................ 35 2.2.1 One pot syntheses ............................................................................................ 35 2.2.2 1,4 Disubstituted cyclo additions..................................................................... 43

3. Experimental ................................................................................................................. 47 3.1 General procedures ................................................................................................. 47 3.2 Synthesis ................................................................................................................. 49

4 Further studies and conclusion....................................................................................... 72 4.1 Further studies......................................................................................................... 72 4.2 Conclusion .............................................................................................................. 73

5. References..................................................................................................................... 74

5

1. Drug development

1.1 Introduction Even though we have come a long way in discovering drugs in many areas of human

diseases, there is still a great demand for new and better drugs. New illnesses come along

that need new drugs to combat them, and drugs that were once efficient are now futile

against many common diseases. This might, for example, be due to resistance among

bacteria. Other reasons to develop new drugs can be that the synthesis of the existing

drug is difficult, expensive or harmful to the environment. Some drugs also have

unacceptable side effects to go along with their wanted effects. Side effects might be

minimized by altering the molecule slightly.

Pharmaceutical companies and academic milieus are constantly putting in a great effort to

discover new pharmaceutical compounds. This is a very laborious task, which in many

cases is done practically “blindfolded” in a trail and error manner. This means that one

needs a vast amount of compounds.

A typical new pharmaceutical compound costs in the area of $800 mill. to develop from

idea to a product ready for marketing (2001).1 Any enhancement in any step of the

development of novel drugs would be of great value to any pharmaceutical company. If

there is a way to avoid one step in the synthesis and purification process, a lot of money

would be saved. This is why a synthetic reaction that is facile and high yielding would be

suitable for preparing a vast amount of new compounds. To screen a large number of new

compounds for possible effects one would need a tremendously large number of workers

or a smart method. High throughput screening (HTS) allows you to investigate thousands

of compounds each day. The principles of HTS will be further discussed later.

6

1.2 Combinatorial chemistry: All of the 10 largest selling drugs in 1994 were small organic molecules, i.e., compounds

with molecular weights less than 700 daltons. 2 Due to this fact, much of the efforts of

drug discovery are focused on small, organic molecules. To synthesize a reasonable

library of compounds it is important to synthesize a great number of them. The traditional

methods of organic chemistry limits chemists productivity a lot. A way to solve this

problem is to do multiple reactions simultaneously. To do multiple reactions at the same

time there are two key challenges that has to be met. First you have to develop reactions

that are reliable and constantly produce satisfactory yields. The reactions should also be

compatible with a large number of starting materials. Once you have found your

preferred reactions, you need to develop a method to efficiently detect and identify your

products.

And the generation of molecular diversity by chemical synthesis is also important in drug

discovery. The generation of molecular diversity is also based on the concepts of peptide

synthesis. It was first reported by Merrifield3 in 1963 that it was possible to obtain good

yields and simple isolation techniques by using polymeric supports for the synthesis of

peptides.

Simultaneous synthesis of many products at the same time in multiple reaction vessels,

often on a plate, is known as parallel synthesis. The concept is to mix and react two

different groups of molecules, for example amines and carboxylic acids. For simplicity,

let us consider a plate that has 4x4 wells. We have 4 amines: A1-A4 and 4 carboxylic

acids: B1-B4. Each amine goes in a horizontal row. And each carboxylic acid goes in a

vertical row. (See Figure 1) As seen in fig.1, we end up with a total of 16 products.

A1B1 A1B2 A1B3 A1B4

A2B1 A2B2 A2B3 A2B4

A3B1 A3B2 A3B3 A3B4

A4B1 A4B2 A4B3 A4B4 Figure 1: Parallel synthesis

7

In combinatorial synthesis one perform multiple reactions in the same vessel. An

example of the simplest way to perform a combinatorial synthesis is one vessel filled

with multiple reactants. If we mix two acids and five amines in a vessel to perform a

amide reaction, we would end up with 2x5= 10 products.. An advance in combinatorial

chemistry came with the portion-mixing approach described by Furka in 19884. This

method is known as the split and mix method. Using this method, we mix the two acids

and divide the mixture into five vessels where we add the five different amines into each

one. We produce a library of compounds that exist in several mixtures. These mixtures

are suitable for analysis with assays. The split and mix method can be utilized to make

vast compound libraries in a short period of time.

In the two techniques described above it is common to attach the reactants to a solid

phase. The solid phase can be beads made of polymeric material. This eases the process

of isolation as well as giving higher yields, and also renders purification unnecessary.

8

1.3 High throughput screening To be able to analyze the enormous number of compounds obtained by using

combinatorial chemistry, a powerful method is needed. A HTS system is built around a

plate with small wells, where samples and assay reagents are deposited. The aim of the

assays is to detect “hits”. A “hit” is a positive result. There can be a variety of detector

systems. They can detect radioactivity, luminescence or fluorescence for example.

Detection of such signals indicates a “hit”, and the strength of them indicate the quality of

the “hit”. MS detection is also used to identify products, even on single beads taken from

a sample.5 If a “hit” is detected, the chemist has to look closer at the compounds in the

well that produced the “hit”.

A HTS system is often set up to be automated. The use of robotics is both time and cost

effective. The chemists’ job is to find the appropriate assay to the library compounds and

program the robotics to deliver the needed samples to the wells on the plate.

9

1.4 Click chemistry

Professor K. B. Sharpless and co-workers at The Scripps Research Institute in 2001

introduced click chemistry as guiding principles for organic synthesis. Click chemistry

was their response to the problems associated with making reliable libraries of potential

lead structures using combinatorial chemistry. Click chemistry is a modular approach to

chemical synthesis that utilizes only the most practical and reliable chemical

transformations.

To fit into the category of click chemistry a reaction has to meet certain requirements. 6,7

1: It has to be a facile and selective reaction.

2: It must be of a wide scope, meaning that it will provide high yields from a large

variety of starting compounds consistently.

3: It must be easy to perform and insensitive to water and oxygen.

4: It must use only readily available reagents.

5: The reaction has to be easy to work up and the product isolation must be simple,

without requiring any chromatography.

Its applications are increasingly found in all aspects of drug discovery, ranging from lead

finding of new drug candidates through proteomics as well as DNA research utilizing

bioconjugation reactions.

Despite many successes, drug discovery approaches that are based on Nature’s secondary

metabolites, i.e. natural products, are often hampered by slow and complex synthesis of

drug candidates. Through the use of only the most facile and selective chemical

transformations, click chemistry simplifies synthesis and purification in medicinal

chemistry based on natural products. This will enable faster discovery of lead molecules,

as well as speed up the optimization of existing biologically active compounds that

targets a specific receptor. Thus, click chemistry is a set of powerful, virtually 100%

10

reliable, selective reactions for rapid synthesis of a vide variety of biologically active

compounds.

Click chemistry uses carbon-heteroatom bond-forming connection chemistry.6 In click

chemistry the focus is on highly energetic reactants and kinetic control of the reaction,

hence click chemistry reactions are also irreversible.

Click reactions utilizes benign reaction conditions. They should work very well in water

and in the presence of oxygen. This is a great advantage because it limits the use of

environmentally unfriendly solvents used in “traditional” chemical synthesis. The fact

that the reactions are insensitive to oxygen makes them a whole lot easier to perform.

There is no need to do them under argon or nitrogen. This limits the effort required. A

huge advantage of click chemistry is that they use strongly driven and highly selective

reactions. The reactions are run at neutral pH or slightly alkaline pH.

Another benefit is that the triazole ring is not just a passive link, it interacts with

biological targets through hydrogen bonding and dipole interactions.6 Many

pharmaceutical compounds include heterocycles as a functional group. Click chemistry

gives access to a vast variety of five and six membered heterocycles through such

reactions as hetero Diels-Alder and 1,3-dipolar cycloadditions8.

The 1,4-disubstitiuted 1,2,3-triazoles prepared by a copper-(I)-catalyzed reaction between

terminal alkynes and azides (Figure 2),9 is an example of a synthesis that produces one of

the hetero cycles mentioned above. This reaction seems well suited for medicinal

chemistry for the rapid development of drug lead compounds. The regioisomeric product

formed, the 1,4-disubstituted 1,2,3-triazole, shares topological and electronic features

with Nature’s ubiquitous amide connectors. Unlike amides, triazoles are not susceptible

to cleavage and are hence stable both in vitro and in vivo.

11

O

NH

R1R2 ~ N

NNR2R1

5.0 Å3.8 Å

Dipole moment: ~ 5.0 Debye

N2 and N3: Weak H bond acceptors

Difficult to oxidize or reduce

Hydrolytically stable

Precipitates easily in aquous solutions

1,4-Disubstituted 1,2,3-triazoles could serve as amide linkers

Physical and chemical properties:

Figure 2: Amides and 1,2,3-triazoles share topological and electronic features

Given the readily access to the starting azides and terminal alkynes, highly diverse and

unambiguous lead compounds should become available quickly, since there are no need

for protection and deprotection steps under click chemistry conditions. Furthermore, with

complete conversion of starting materials and with exclusive selectivity for the 1,4-

disubstituted 1,2,3-triazoles, the process of identification and discovery of new drug lead

compounds, as well as optimization of existing ones, should become more efficient.

Because click chemistry relies on a small number of near perfect reactions there is some

concern that there will be limits to the potential chemical diversity of the compound

libraries obtained by using the procedures. In a computational study by Guida et al. it is

suggested that the number of drug like compounds are as large as 1063.10 A drug like

compound has less than 30 non H-atoms, a size less than 500 daltons and includes only

H, C, N, O, P, S, F, Cl and Br and they must be likely to be stable in presence of water

and oxygen. At this point somewhere between 106 and 107 such molecules are known.

This means that only a very small part of the potential drugs have been discovered. Click

chemistry can’t explore all of these possibilities, but it is a fast and effective way to

explore a huge number of interesting molecules that can be made with relative ease. In

this way research can focus on the part of the 1063 different molecules that are easy to

make and isolate rather then starting with the ones that requires complex synthesis.

12

The Huisgen 1,3-dipolar cycloadditions of azides and alkynes to give triazoles, is a useful

cycloaddition reaction that gives heterocycles.11 Even though the reaction is favored

kinetically, it may require elevated temperature and it usually results in a mixture of the

1,4 and 1,5 regioisomers.

Figure 3: Regioisomers of 1,2,3-triazoles11(Reprinted)

Efforts to control this 1,4- versus 1,5 regioselectivity problem was met with various

success until the copper(I)-catalyzed reaction was discovered.11 While a number of

copper(I) sources can be used, it was found that the catalyst was better prepared in situ by

reduction of copper(II) salts. Copper sulphate serves well as a source. As the reductant,

ascorbic acid or sodium ascorbate proved to be excellent. With 0.25-2% mol of the

copper(I) catalyst the reaction is regiospecific at ambient temperatures and yields only the

1,4-disubstituted 1,2,3-triazoles.11

The mechanism proposed by Rostovtsev et al. is shown in Figure 4. It starts with the

formation of the copper (I) acetylide. Functional theory calculations and experimental

work published by Sharpless et al. in 200512 points to a stepwise, annealing sequence

rather than the concerted [2+3] cycloaddition.

13

Figure 4: Mechanism of copper(I) catalysis. Reprinted11

14

1.5 Synthesis of starting compounds

Terminal alkynes can be synthesized in numerous ways. Some common procedures will

be outlined here.

McKelvie reported the synthesis of 1,1-dibromoolefins (ylide) via phosphine-

dibromomethylenes in 1962.13 (Figure 5) This discovery was important for future work.

C B r4 2 (C 6 H 5 )3 P (C6H5)3P CBr2 (C 6 H 5 )3 PB r2

C6H5

C6H5 C CBr2

H

C O

H

(C 6 H 5 )3 P O

Figure 5: A 1,1-dibromoolefin In 1972 Corey and Fuchs synthesized terminal alkynes from aldehydes.14 The synthesis

involves 2 steps. (Figure 6) Notice that the first step is the same as in Figure 5.

R H

OPh3P, CBr4

Br Br

RH

1. BuLi

2. H2OR

Figure 6: Corey-Fuchs synthesis of terminal alkynes

Colvin and Hamill reported a one-step conversion of carbonyl compounds into acetylenes

in 1973.15 (Figure 7)

15

or

Si

CH3

H3C

CH3

H

N

P

O

H3CO

OCH3 N

N

H

R1

O

R2

baseR1 R2 N2

Si O

CH3

H3C

CH3

or P

O

OH3CO

OCH3

N

Figure 7: Colvin and Hamill conversion.

Ohira reported a useful means of preparing dimethyl (diazomethyl)-phosphonate.16

(Figure 8)

O

N2

P

O

OCH3

OCH3

H

N2

P

O

OCH3

OCH3

0.2 eq. K2CO3

MeOH, 0ºC

Figure 8

Bestmann reported a one pot procedure for preparing terminal alkynes with the reagent

dimethyl-1-diazo-2-oxopropylphoshonate.17 (Figure 9)

16

O

N2

P

O

OCH3

OCH3

r.t., 4-16tR

O

H

K2CO3, MeOHR

Figure 9

Azides are readily accessible through numerous reactions. One way to obtain azides are

nucleophilic substitution reactions. (SN2 type.) These and other ways to obtain azides are

thoroughly reviewed in “Organic Azides: An Exploding Diversity of a Unique Class of

Compounds”.18

17

1.6 Tubulin and tubulin inhibitors

Every nucleated cell in the human body contains two similar spherical proteins called α

and β tubulin. These two come together to form an α- β heterodimer. These heterodimers

can, in the presence of GTP at 37oC, form long protein fibers called protofilaments.

These protofilaments group together and curl up to form pipe-like structures called

microtubules.19 The microtubules give the cell support, acting like a scaffold. They also

organize the organelles of the cell. The most important role of the microtubules is the

formation of the mitotic spindle. The mitotic spindle is involved in the cell replication

process, where it “pulls” the chromosomes towards opposite sides of the dividing cell.

(Figure 10)

Figure 10: Microtubules in mitosis. Reprinted20 In cancer cells the cell replication process is out of control.19 One target for controlling

the growth of a tumor is therefore to inhibit the formation of microtubules. There are

separate classes of drugs that bind to tubulin. All tubulin inhibiting substances are divided

18

fit into classes depending upon the effect which that substance exerts on the binding site

of five characterized tubulin agents to tubulin. These agents are colchicine, vincristine,

vinblastine, rhizoxin and myatansine.19

Combretastatin A-4(Figure 11) is isolated from the South African Willow, Combretum

caffrum, and has a simple chemical structure that shows antimitotic effect by interaction

with the colchicine binding site on tubulin.21 Combretastatin A-4 has shown an

impressive spectrum of activity, including inhibition of angiogenesis, which is essential

for tumor growth.22 Combretastatin A-4 has been considered for clinical trails, but these

met an obstacle due to the poor water solubility of the drug. There is currently being done

a lot of research to make analogues that overcome this problem.

MeO

MeO

OMe

OMe

OH

Figure 11: Combretastatin A-4

19

1.7 Sulfonamides

In the early 1930s Gerhard Domagk tested a variety of azo dyes for antibacterial activity.

Prontosil showed significant results in test. The dye successfully protected mice against

streptococcal infections.23 Later Tréfouël found that prontosil was not active in vitro, but

when a reducing agent was added the drug was active.24 It was found that prontosil

needed to be reduced to sulfanilamide to be active. The discovery of prontosil, and its

properties, marks the beginning of modern chemotherapy and structure-activity

relationship studies.

A breakthrough in the discovery of the mechanism of action for the sulfonamides was

made in 1940 by Woods.25 He showed that the p-aminobenzoic acid was a potent

inhibitor of sulfanilamide induced bacteriostasis in streptococcal infected mice. Finally,

Miller demonstrated that sulfanilamide inhibited the folic acid biosynthesis, that is critical

for the growth of bacteria.26

A major concern with the use of sulfonamide drugs is the development of drug resistance.

One mechanism of drug resistance is that the bacteria develop an enzyme that is less

sensitive to sulfonamides than p-aminobenzoic acid.27 Another mechanism involves

altered permeability to the sulfonamides.28 Synthesis of analogues that avoid these

problems could prove very valuable.

20

Figure 12: Biochemical reaction catalyzed by dihydropteroic synthetase29 (reprinted).

Biochemical synthesis of dihydropteroic acid is shown in Figure 12. The various

sulfonamide analogs inhibit this synthetic pathway by competitive inhibition of PABA.

The sulfonamides have a similar structure to PABA and therefore they can interfere in the

reaction shown in Figure 12. Dihydropteroic acid is essential to the formation of folic

acid that is required as precursors in the synthesis of both DNA and RNA in bacteria and

mammals.

21

1.8 Aim of study In the present study it is sought to synthesize 1,2,3-triazole analogues of combretastatins

and antibacterial sulfonamides. In addition, another aim was to see if new one-pot click

chemistry procedures could be developed.

OH

OMe

OMe

MeO

MeO

Combretastatin A-4 MeO

MeO

OMe

N

N

N

HO O

O

Click chemistry

MeO

OMe

OMe

HO

N3

O

O

Figure 13: Example of synthesis of a combretastatin analogue

S

O

ONH

HN O

O

BrOBr

S

O

ONH

HN O

OBr

O

N

N N

Click chemistry

H2N SO2NH2

Sulfanilamide

Figure 14: Example of synthesis of a sulfanilamide analogue

22

2. Results and Discussion

2.1 Syntheses

2.1.1 Syntheses of alkynes

The first object of the study was to synthesize the starting materials. To obtain alkynes a

reduction from 3,4,5-trimethoxybenzaldehyde to (3,4,5-trimethoxyphenyl)methanol (1)

was performed, as outlined in Equation 1.

MeO

OMe

OMe

CH2OH

MeO

OMe

OMe

CHO

NaBH4

EtOH:H2O, 1:1THF

Equation 1 1 (100%)

The product had a Rf in hexane:EtOAc (2:1) of 0.13. 1H NMR spectra of the product

showed a singlet at 6.58 ppm with an integral height of 2 that indicated two aromatic

protons. A singlet at 4.62 ppm with an integral height of 2 indicated two protons in α-

position to a benzene ring. Two singlets at 3.85 ppm and 3.82 ppm with integral heights

of 6 and 3 indicated nine methyl protons. There was no signal for the proton on the

alcohol group. 13C NMR data showed a peak at 153.30 ppm that indicated two aromatic

carbons. Two peaks at 137.23 ppm and 136.63 ppm representing two aromatic carbons.

At 103.75 a peak represented two aromatic carbons. A peak at 65.43 ppm indicates an

aliphatic carbon. At 60.80 ppm and 56.03 ppm two peaks for the three methyl carbons

were shown.

23

The product 1 was used to synthesize 5-(bromomethyl)-1,2,3-trimethoxybenzene (2), as

shown in Equation 2

MeO

OMe

OMe

CH2Br

MeO

OMe

OMe

CH2OH

Equation 2 2 (58%)

The melting point of 2 determined to 74-75oC. Rf in hexane:EtOAc (9:1): 0.65; 1H NMR

spectra of the product 2 showed a singlet at 6.62 ppm with an integral height of 2 that

indicated two aromatic protons. A singlet at 4.46 ppm with an integral height of 2

indicated two protons in α position to a carbon-carbon double bond. Two singlets at 3.87

ppm and 3.84 ppm with integral heights of 6 and 3 indicated nine methyl protons.

The product 2 was used in an attempt to synthesize 1,2,3-trimethoxy-5-(prop-2-

ynyl)benzene (3), as shown in Equation 3.

MeO

OMe

OMe

CH2Br

MeO

OMe

OMe

MgBrCCH

CuI, 0oC

Equation 3 3 (0%)

24

The reaction outlined in Equation 3 was monitored by TLC after 1 hour there was no sign

of formation of the product. The temperature was elevated to 58oC and the mixture was

left to stir for 48 h. A new test by TLC showed that no product was formed and the

experiment was aborted.

A Grignard reaction to obtain a terminal alkyne, as outlined in Equation 4, was

performed.

OMe

OMeMeO

OMe

MeO

O

OHMeCuI, 0oC

HO

MgBrCCH

Equation 4 4 (88%)

The product 1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (4) obtained was not pure. After

column chromatography, an 88% yield of 4 was collected. Rf in hexane:EtOAc (1:1):

0.42. 1H NMR spectra of the product showed a singlet at 6.80 ppm with an integral height

of 2 indicated two aromatic protons. A singlet at 5.42 ppm with an integral height of 1

indicated a methinine proton. Two singlets at 3.89 ppm and 3.85 ppm with integral

heights of 6 and 3 indicated nine methyl protons. A doublet at 2.69 ppm (J 2.1 Hz)

indicated an alcohol proton. 13C NMR data showed a peak at 153.87 ppm that indicated

two aromatic carbons. Two peaks at 138.10 ppm and 135.56 ppm represented two

aromatic carbons. At 103.64 a peak represented two aromatic carbons. Two peaks at

83.56 ppm and 74.89 ppm indicated two acetylene carbons. At 64.56 ppm a peak

indicated an aliphatic carbon. At 60.84 ppm and 56.15 ppm two peaks for the three

methyl carbons were shown. This confirmed the structure of 4.

25

Another terminal alkyne was prepared, this time utilizing dry conditions. The reaction

(Equation 5) produced 5-ethynyl-1,2,3-trimethoxybenzene (5) in 64% yield after

purification by column chromatography.

H3CO

OCH3

OCH3

O

H3CO

OCH3

OCH3

C4H10N2Si

[(CH3)2CH]2NLi,

-78oC

THF

Equation 5 5 (64%)

The melting point of 5 was found to be 93-95oC. Rf in hexane:EtOAc (8:3): 0.50. 1H

NMR spectra of the product showed a singlet at 6.73 ppm with an integral height of 2 that

indicated two aromatic protons. A singlet at 3.85 ppm with an integral height of 9

indicated nine methyl protons. A singlet at 3.03 ppm with an integral height of 1

indicated an acetylene proton. 13C NMR data showed a peak at 153.04 ppm that indicated

two aromatic carbons. Two peaks at 139.30 ppm and 117.01 ppm represented two

aromatic carbons. At 109.36 a peak represented two aromatic carbons. Two peaks at

83.70 ppm and 76.19 ppm indicated two acetylene carbons. At 60.95 ppm and 56.15 ppm

two peaks for the three methyl carbons were shown. HRMS data showed that molecular

ion was observed at 192.0780 daltons. This confirmed the structure of 5.

An example of a N-acylation of propargylamine with an acyl chloride to yield ethyl prop-

2-ynylcarbamate (6) is shown in Equation 6.30

26

H2NO

O ClNH

O

O

CH2Cl2

Equation 6 6 (0%)

A NMR of the product (6) indicated that only starting materials was isolated.

The N-acylation of propargylamine was performed in the same matter as shown in

Equation 6 using a sulfanilylchloride as the other reagent. This reaction is shown in

Equation 7.

H2N

S

O

ONH

HN O

S

O

O

HN O

Cl

Pyridine0oC

Equation 7 7 (43%)

The reaction yielded N-(4-(N-prop-2-ynylsulfamoyl)phenyl)acetamide (7). This reaction

was performed both on a small scale and a larger scale, using 2 mmol and 45 mmol of

propargylamine. The yields were 24% for the small scale reaction and 43% for the larger

scale reaction. The structure of the product 7 was assigned based on NMR and MS data

as well as the melting point. The melting point was determined to 192-193oC. Rf in

hexane:EtOAc (1:5): 0.40. 1H NMR spectra of the product showed a singlet at 9.50 ppm

with an integral height of 1 that indicated a sulfonamide proton. A multiplet at 7.84-7.77

ppm with an integral height of 4 indicated four aromatic protons. A multiplet at 3.81-3.79

ppm with an integral height of 2 indicated two methylene protons. A singlet at 2.12 ppm

with an integral height of 3 indicated 3 methyl protons. A singlet at 2.09 ppm with an

integral height of 1 indicated a secondary amine proton. 13C NMR data showed a peak at

170.50 ppm that indicated an amide carbon. Four peaks at 145.15 ppm, 136.45 ppm,

27

130.08 and 120.37 indicated six aromatic carbons. Two peaks at 80.73 ppm and 74.63

ppm indicated two acetylene carbons. Two peaks at 34.13 ppm and 25.38 ppm indicated

two aliphatic carbons. HRMS data showed the molecular ion at 252.0565. This confirmed

the structure of 7.

S

O

O

N+

O

O-

HNS

O

O

N+

O

O-

Cl

NH2

H2O, pH 820oC

Equation 8 8 (61%)

The structure 4-nitro-N-(prop-2-ynyl)benzenesulfonamide (8) was assigned based on

NMR and MS data as well as the melting point. The melting point was determined to

152-154oC. Rf in hexane:EtOAc (2:1): 0.33. 1H NMR data showed a triplet at 8.54 ppm (J

5.8) with an integral height of 1 that indicated a sulfonamide proton. Two multiplets at

8.45-8.38 ppm and 8.09-8.04 ppm with integral heights of 2 represented four aromatic

protons. A doublet of a doublet at 3.79 ppm (J 2.6) with an integral height of 2

represented two aliphatic protons. A triplet at 3.01 ppm (J 2.6) with an integral height of

1 represented an acetylene proton. 13C NMR data showed four peaks at 149.53 ppm,

146.18 ppm, 128.34 ppm, 124.29 ppm that represented six aromatic carbons. Two peaks

at 78.72 ppm and 75.09 ppm represented two acetylene carbons. A peak at 31.81 ppm

indicated an aliphatic carbon.

An alkaline hydrolysis of 7 to yield 4-amino-N-(prop-2-ynyl)benzenesulfonamide (9) was

performed as outlined in Equation 9.

28

S

O

ONH

HN O

NaOH

100oC S

O

ONH

NH2

O

O-

Equation 9 9 (0%)

TLC of the reaction mixture showed that a product was formed, but there were

difficulties with the isolation of the product. It would not be distributed in the organic

phase when an extraction with chloroform and water was attempted. The water phase was

evaporated under reduced pressure and the resulting solid was dissolved in methanol. The

solution was filtered through a “plug”. (Figure 15)

Figure 15: The plug used for filtration of 8

The methanol was evaporated under reduced pressure. The crude product was believed to

be a mixture of 9 and sodium chloride, where the sodium chloride originated from the

neutralization of the reaction mixture with hydrochloric acid. Rf in hexane:EtOAc (1:4)

was 0.38. 1H NMR spectra of the product 9 showed a doublet at 7.53 ppm (J 8.7 Hz) with

an integral height of 2 that indicated two aromatic protons. A doublet at 6.69 ppm (J 9.0

Hz) with an integral height of 2 indicated two aromatic protons. A doublet at 3.65 ppm (J

2.7 Hz) with an integral height of 2 indicated two methylene protons. A triplet at 2.47

ppm (J 2.7 Hz) with an integral height of 1 indicated a secondary amine proton. A singlet

at 2.16 ppm with an integral height of 1 indicated an acetylene proton. 13C NMR data

showed four peaks at 154.28 ppm, 130.92 ppm, 127.12 and 114.43 that indicated six

aromatic carbons. Two peaks at 79.93 ppm and 73.34 ppm indicated two acetylene

carbons. At 33.18 ppm a peak indicated an aliphatic carbon. The NMR data showed that

29

the product was formed, but there were difficulties with the isolation of the product.

HRMS data indicated a molecular ion at 210.0457.

2.1.2 Syntheses of azides.

Several azides were synthesized by nucleophilic substitution (SN2 type). Ethyl 2-

azidoacetate (10) was synthesized as outlined in Equation 10.

NaN3

O

OBr EtOH:H2O (1:1)

O

ON3 Equation 10 10 (55%) 1H NMR spectra of the product 10 showed a quartet at 4.24 ppm (J 6.9 Hz) with an

integral height of 2 that indicated two aliphatic protons. A singlet at 3.84 ppm with an

integral height of 2 represented the two protons in α-position to the azido group. A

doublet 1.29 ppm (J 6.9 Hz) with an integral height of 3 indicated three methyl protons. 13C NMR data showed a peak at 168.21 ppm that represented a carboxylic carbon. Two

peaks at 61.79 ppm and 50.29 ppm represented two aliphatic carbons. A peak at 14.05

represented a methyl carbon. HRMS data indicated the molecular ion at 129.0539. IR

data showed signals at 2109 cm-1 for the azido group and 1747 cm-1 for the carbonyl

carbon. This confirmed the structure of 10.

Synthesis of (azidomethyl)benzene (11). (Equation 11)

Br N3

NaN3

EtOH:H2O (1:1)

Equation 11 11 (86%)

30

The product 11 had a Rf of 0.80 in hexane:EtOAc (2:1); 1H NMR spectra showed

multiplet at 7.43-7.30 ppm with an integral height of 5 that indicated five aromatic

protons. A singlet at 4.35 ppm with an integral height of 2 represented the two protons in

α-position to the azido group. 13C NMR data showed four peaks at 135.35, 128.82,

128.29 and 128.20 ppm that represented six aromatic carbons. A peak at 54.80 ppm

represented a carbon α-position to the azido group. The product was a yellow liquid.

Synthesis of 1-(azidomethyl)-4-nitrobenzene (12) (Equation 12).

NaN3

N+O O-

Br

N+O O-

N3

EtOH:H2O (1:1)

Equation 12 12 (89%) The product 12 had a Rf of 0.80 in hexane:EtOAc (2:1); 1H NMR spectra showed

multiplet at 8.26-8.19 ppm with an integral height of 2 that indicated 2 aromatic protons.

A multiplet at 7.58-7.48 ppm with an integral height of 2 indicated 2 aromatic protons. A

singlet at 4.51 ppm with an integral height of 2 represented the two protons in α-position

to the azido group. 13C NMR spectrum data showed four peaks at 144.74, 142.67, 129.89

and 124.03 ppm that represented six aromatic carbons. A peak at 53.72 ppm represented

a carbon α-position to the azido group. The product was a yellow liquid. HRMS indicated

a molecular ion at 178.0490.

In these experiments it was important to monitor the pH of the mixture before the NaN3

was added. In acidic aqueous solutions NaN3 will produce the highly toxic and explosive

HN3. The experiments were straight forward to perform, and the products were easily

isolated via extraction with EtOAc and evaporation under reduced pressure.

31

Another method for preparation of azides was attempted. A direct conversion of activated

alcohols to azides.31 (Equation 13 and Equation 14)

OH

N

DBU

(PhO)2PON3

N3

N

Equation 13 13 (0%)

DBU

(PhO)2PH2ON3

N3OH

N N

Equation 14 14 (0%) These two reactions proved difficult to perform and no product was isolated in either one

of them.

2.1.3 Desalting of 3-(bromomethyl-)pyridine hydrobromide An attempt to synthesize 3-(bromomethyl)pyridine (15) was made. (Equation 15)

N

Br

NaOH

H2O:EtOH, 1:1

HBr

N

Br

x HBr

Equation 15 15 (0%)

No product 15 was found when the reaction (Equation 15) was monitored with TLC.

32

2.1.4 Syntheses of bromides

O

BrCl

HO

Br

O

BrOBr

Triethylamine


The product, 2-bromophenyl 2-bromoacetate (16) was obtained as a colorless liquid after

column chromatography (Equation 16). The product 16 had a Rf of 0.60 in hexane:EtOAc

(3:1). 1H NMR spectra showed a doublet at 7.62 ppm (J 7.8 Hz) with an integral height of

1, a triplet at 7.35 ppm (J 8.1 Hz) with an integral height of 1 and a multiplet at 7.18-

7.13 ppm with an integral height of 2. These three signals represented four aromatic

protons. A singlet at 4.37 ppm with an integral height of 2 indicated two aliphatic

protons. 13C NMR data showed a peak at 164.96 ppm that represented a carboxylic

carbon. Six peaks at 147.62 ppm, 133.44 ppm, 128.59 ppm, 127.85 ppm, 123.31 ppm and

115.71 ppm represented six aromatic carbons. At 25.05 ppm a peak indicated an aliphatic

carbon.

O

BrCl

OBr

O

O

O

HO

O

Otriethylamine


Methyl 3-(4-(2-bromoacetoxy)phenyl)propanoate (17) was isolated after column

chromatography (Equation 17). The product 17 had a Rf of 0.38 in hexane:EtOAc (3:1); 1H NMR spectra showed a doublet at 7.23 ppm (J 8.7 Hz) with an integral height of 2 and

a doublet at 7.05 ppm (J 8.7 Hz) with an integral height of 2. These two signals

represented four aromatic protons. A singlet at 4.27 ppm with an integral height of 2

indicated two aliphatic protons. A singlet at 3.67 ppm with an integral height of 3

33

indicated three methyl protons. A triplet at 2.96 ppm (J 8.1 Hz) with an integral height of

2 represented 2 aliphatic protons. A triplet at 2.63 ppm (J 7.8 Hz) with an integral height

of 2 represented two aliphatic protons. 13C NMR spectrum data showed two peaks at

173.06 ppm and 165.91 that represented two carboxylic carbons. Four peaks at 148.71

ppm, 138.71 ppm, 129.41 ppm and 121.07 ppm represented six aromatic carbons. At

51.65 ppm a peak represented a methyl carbon. At 40.85 ppm, 35.52 ppm and 30.25 ppm

three peaks indicated three aliphatic carbons.

34

2.2 Click reactions

2.2.1 One pot syntheses

Several one pot syntheses was performed to yield 1,4-disubstituted 1,2,3-triazoles. They

were performed as described in general procedures for one-pot click reactions. The

reactions and results are discussed below.

MeO

MeO

OMe

N

NN

O

OMeO

OMe

OMe

OBr

O

CuSO4NaAscorbatet-BuOH:H2O, 1:1

NaN3

Equation 18 18 (51%) The synthesis of ethyl 2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)acetate (18)

did not go to completion after 12 hours of stirring at room temperature. Another 0.5 eqv.

of the azide along with more of the sodium ascorbate and the copper sulphate catalyst

was added and the mixture was allowed to stir for two more days.. The TLC still

indicated traces of the starting materials. Total yield of the reaction was 51%. The

melting point was determined to 95-97oC. Rf in hexane:EtOAc (1:10) was 0.66. 1H NMR

spectra of the product 18 showed a singlet at 7.90 ppm with an integral height of 1 that

represented the triazole proton. A singlet at 7.06 ppm with an integral height of 2

represented two aromatic protons. A singlet at 5.20 ppm with an integral height of 2

indicated two aliphatic protons. A quartet at 4.29 ppm (J 7.8 Hz) with an integral height

of 2 represented two aliphatic protons. Two singlets at 3.92 ppm and 3.87 ppm with

integral heights of 6 and 3 indicated nine protons on the methoxy groups. A triplet at 1.31

ppm (J 7.8 Hz) with an integral height of 3 represented three methyl protons. 13C NMR

spectrum data showed a peak at 166.27 ppm that represented a carboxylic carbon. Three

peaks at 153.62 ppm, 138.24 ppm and 125.84 ppm represented four aromatic carbons. At

120.77 ppm a peak indicated a triazole carbon. At 103.04 a peak indicated two aromatic

35

carbons. At 62.50 a peak represented an aliphatic carbon. At 60.92 ppm and 56.24 ppm

two peaks represented the three carbons in the methoxy groups. At 50.97 ppm and 14.06

ppm two peaks indicated two aliphatic carbons. A peak for the second triazole carbon

was not found in the spectrum. HRMS data indicated a molecular ion at 321.1330.

MeO

OMe

OMe

OBr

O


HO

OMeMeO

MeO

HO

NN

N

O

O

NaN3

Equation 19 19 (0%) NMR data of ethyl 2-(4-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1H-1,2,3-triazol-1-

yl)acetate (19) (Equation 19) showed that only starting materials were isolated.

Synthesis of diethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)malonate (20) outlined in Equation

20.

O

O

O

O

Br

NaN3

CuSO4,NaAscorbat

NN

N

O

O

O

O

H2O:t-BuOH, 1:1

Equation 20 20 (25%) The NMR data showed that the product (20) obtained was not pure. (Equation 20)

36

O

OBr NaN3

CuSO4,NaAscorbatt-BuOH:H2O, 1:1

N

N

N O

O

Equation 21 21 (36%) The NMR data showed that ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoate (21)

obtained was not pure. (Equation 21)

NaN3


N

NN

O

O

BrO

O

Equation 22 22 (61%) Synthesis of ethyl 2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (22) (Equation 22).

NMR data showed that the product was not formed.

37

S

O

ONH

HN O

O

BrOBr

NaN3

CuSO4NaAscorbate

S

O

ONH

HN O

OBr

O

N

N N

t-BuOH:H2O, 1:1

Equation 23 23 (38%) NMR data of 2-bromophenyl 2-(4-((4-acetamidophenylsulfonamido)methyl)-1H-1,2,3-

triazol-1-yl)acetate (23) (Equation 23) showed that no product was isolated.

O

BrOBr

NaN3

CuSO4NaAscorbate

O

BrO

N

N

N

t-BuOH:H2O, 1:1

Equation 24 24 (0%) Synthesis of 2-bromophenyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (24). (Equation

24) TLC monitoring of the reaction showed that no product was formed.

38

NaN3

CuSO4NaAscorbateO2N

O

OBr O2N

O O

N

N

Nt-BuOH:H2O, 1:1

Equation 25 25 (53%) Synthesis of ethyl 2-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)acetate (25) (Equation 25).

The melting point was determined to 144-145oC. Rf in hexane:EtOAc (1:4) was 0.66 1H NMR spectra of the product 25 showed a singlet at 8.85 ppm with an integral height

of 1 that represented the triazole proton. A doublet at 8.32 ppm (J 9.0 Hz) with an

integral height of 2 represented two aromatic protons. A doublet at 8.14 ppm (J 9.0 Hz)

with an integral height of 2 represented two aromatic protons. A singlet at 5.52 ppm with

an integral height of 2 indicated two aliphatic protons. A quartet at 4.21 ppm (J 7.2 Hz)

with an integral height of 2 represented two aliphatic protons. A triplet at 1.24 ppm (J 7.2

Hz) with an integral height of 3 represented three methyl protons. 13C NMR data showed

a peak at 166.98 ppm that represented a carboxylic carbon. At 146.59 ppm a peak

indicated a triazole carbon. Two peaks at 144.38 ppm and 136.79 ppm represented two

aromatic carbons. At 128.33 ppm a peak indicated a triazole carbon. At 125.94 ppm and

124.23 ppm two peaks indicated four aromatic carbons. At 61.58 ppm and 50.63 ppm two

peaks indicated two aliphatic carbons. At 13.89 ppm a peak indicated a methyl carbon.

The reaction gave a mixture of the product and the starting materials. The starting

materials showed up in the NMR spectrums. Hence, the yield was lower than expected

for standard click reactions.

39

O

OBr

O O

N

N

NF

F

NaN3


Equation 26

26 (42%)

Synthesis of ethyl 2-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)acetate (26). (Equation 26)

The reaction was straight forward, but the yield was lower than expected for standard

click reactions. The melting point was found to be over 250oC. Rf in hexane:EtOAc (1:4)

was 0.72; 1H NMR spectra of the product 26 showed a singlet at 8.68 ppm with an

integral height of 1 that represented the triazole proton. A multiplet at 7.72-7.14 ppm

with an integral height of 4 represented four aromatic protons. A singlet at 5.47 ppm with

an integral height of 2 indicated two aliphatic protons. A quartet at 4.20 ppm (J 7.2 Hz)

with an integral height of 2 represented two aliphatic protons. A triplet at 1.04 ppm (J 7.2

Hz) with an integral height of 3 represented three methyl protons. HRMS data indicated

the molecular ion at 249.0913.

O

OBr

O O

N

N

N

NaN3

CuSO4NaAscorbatet-BuOH:H2O, 1:140oC

O2N

O2N


Synthesis of ethyl 2-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)acetate (27) (Equation 27).

40

This reaction was a repetition of the one shown in Equation 25 with an elevated

temperature. The temperature was now set to 40oC to see if it would result in a better

yield. The yield was improved from 53% to 87%, which is in the range for a click

reaction. The melting point was determined to 144-145oC. Rf in hexane:EtOAc (1:4) was

0.66 1H NMR spectra of the product (27) showed a singlet at 8.84 ppm with an integral

height of 1 that represented the triazole proton. Two doublets at 8.33 ppm (J 9.0 Hz) and

8.14 ppm (J 9.0 Hz), both with an integral height of 2 represented four aromatic protons.

A singlet at 5.14 ppm with an integral height of 2 indicated two aliphatic protons. A

quartet at 4.21 ppm (J 7.2 Hz) with an integral height of 2 represented two aliphatic

protons. A triplet at 1.24 ppm (J 7.2 Hz) with an integral height of 3 represented three

methyl protons. These results were in concordance with the results for 25.

S

O

ONH

HN

ONaN3

CuSO4,NaAscorbat

O

OBr

NN

NO

O

S

O

ONH

HN O

Equation 28 28(88%)

Synthesis of ethyl 2-(4-((4-acetamidophenylsulfonamido)methyl)-1H-pyrazol-1-

yl)acetate (28) (Equation 28). The product was isolated as white crystals. The melting

point was determined to 176-178oC. 1H NMR spectra of the product 28 showed a singlet

at 10.31 ppm with an integral height of 1 that represented a secondary amide proton. A

singlet at 8.03 ppm with an integral height of 1 indicated a sulfonamide proton. A singlet

at 7.92 ppm with an integral height of 1 indicated a triazole proton. A multiplet at 7.80-

7.65 ppm with an integral height of 4 indicated four aromatic protons. A singlet at 5.32

ppm with an integral height of 2 represented two aliphatic protons. A quartet at 4.17 ppm

(J 7.1 Hz) with an integral height of 2 represented two protons in α-position to the ester.

A singlet at 4.03 with an integral height of 2 represented two aliphatic protons. A singlet

at 2.09 with an integral height of 3 represented three methyl protons. A triplet at 1.22 (J

41

7.1 Hz) with an integral height of 3 represented three methyl protons. 13CNMR data

showed two peaks at 168.87 and 167.07 that indicated two carbonyl carbons. Four peaks

at 142.67, 133.82, 127.64 and 124.61 represented 6 aromatic carbons. A peak at 118.48

represented a triazole carbon. Five peaks at 61.35, 50.17, 38.60, 24.04 and 13.88

represented five aliphatic carbons. There was not found a peak for the second triazole

carbon. HRMS calcd. for C15H19N5O5S [M+]: 381.1107, found: 381.1074

42

2.2.2 1,4 Disubstituted cyclo additions

S

O

O

N+

O

O-

NH

N3

S

O

O

N+

O

O-

NH

NN

N

NaAscorbateCuSO4t-BuOH:H2O, 1:1

Equation 29 29 (74%) Synthesis of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-4-nitrobenzenesulfonamide (29).

The melting point was determined to 144-145oC. Rf in hexane:EtOAc (1:4) was 0.56 1H NMR spectra of the product 29 showed a singlet at 8.53 ppm with an integral height

of 1 that represented the sulfonamide proton. A doublet at 8.31 ppm (J 9.0 Hz) with an

integral height of 2 represented 2 benzene protons. A doublet at 7.97 ppm (J 9.0 Hz)

with an integral height of 2 represented two benzene protons. At 7.90 ppm a singlet with

an integral height of 1 represented a triazole proton. A multiplet at 7.35-7.22 ppm with an

integral height of 5 represented five aromatic protons. A singlet at 5.49 ppm with an

integral height of 2 indicated two aliphatic protons. A singlet at 4.14 ppm with an integral

height of 2 indicated two aliphatic protons 13C NMR data showed four peaks at 149.32

ppm, 146.10 ppm, 135.80 ppm and 128.58 ppm that represented five aromatic carbons.

At 128.06 ppm a peak indicated a triazole carbon. Four peaks at 127.99 ppm, 127.83

ppm, 124.29 and 123.34 ppm indicated seven aromatic carbons. At 52.59 ppm and 37.83

ppm two peaks indicated two aliphatic carbons. One of the peaks for the carbons on the

triazole did not show up in the spectrum.

43

S

O

O

N+

O

O-

NHN3

S

O

O

N+

O

O-

NH

N

NN

O2N

O2N

NaAscorbateCuSO4t-BuOH:H2O, 1:1


The reaction outlined in Equation 30 was performed twice. The first time over, the

product obtained was impure. This was probably due to insufficient use of solvent. Only

4 mL was used. 8 mL of solvent was used in the second experiment. The reaction gave 4-

nitro-N-((1-(4-nitrobenzyl)-1H-1,2,3-triazol-4-yl)methyl)benzenesulfonamide (30) in a

52% yield. The melting point was determined to 183-185oC. Rf in hexane:EtOAc (1:4)

was 0.36. 1H NMR spectra of the product 30 showed a singlet at 8.58 ppm with an

integral height of 1 that represented the sulfonamide proton. A doublet at 8.31 ppm (J 8.7

Hz) with an integral height of 2 represented two benzene protons. A doublet at 8.22 ppm

(J 8.7 Hz) with an integral height of 2 represented two aromatic protons. At 7.99 ppm (J

8.4 Hz) a doublet with an integral height of 3 represented two aromatic protons and an

overlapping triazole proton. A doublet at 7.47 ppm (J 8.7 Hz) with an integral height of 2

represented two aromatic protons. A singlet at 5.69 ppm with an integral height of 2

indicated two aliphatic protons. A singlet at 4.17 ppm with an integral height of 2

indicated two aliphatic protons. 13C NMR data showed four peaks at 149.26 ppm, 147.11

44

ppm, 146.08 ppm and 143.15 ppm that represented four aromatic carbons. Four peaks at

128.88 ppm, 127.97 ppm, 124.26 ppm and 123.70 ppm represented eight aromatic

carbons. At 58.91 ppm and 37.82 ppm two peaks represented two aliphatic carbons.

S

O

OCl

N+

O

O-

N3

S

O

O

N+

O

O-

NH

NN

N

MeO

MeO

MeO

OMe

MeO

MeO

NH2

CuSO4NaAscorbateEtOH


Synthesis of 4-nitro-N-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-4-

yl)methyl)benzenesulfonamide (31) (Equation 31). The melting point was determined to

148-154oC. Rf in hexane:EtOAc (1:4) was 0.32. 1H NMR spectra of the product 31

showed a singlet at 8.51 ppm with an integral height of 1 that represented the

sulfonamide proton. A doublet at 8.34 ppm (J 9.0 Hz) with an integral height of 2

represented two aromatic protons. A doublet at 8.00 ppm (J 9.0 Hz) with an integral

height of 3 represented two aromatic protons and an overlapping triazole proton. A

singlet at 6.67 ppm with an integral height of 2 represented two aromatic protons. A

singlet at 5.41 ppm with an integral height of 2 indicated two aliphatic protons in α-

position to benzene. A singlet at 4.12 ppm with an integral height of 2 indicated two

aliphatic protons in α-position to the triazole. Two singlets at 3.75 ppm and 3.63 ppm

with integral heights of 6 and 3 indicated nine methoxy protons. 13C NMR data showed

three peaks at 152.90 ppm, 149.39 ppm and 145.95 ppm that represented four aromatic

carbons. At 143.20 ppm a peak indicated a triazole carbon. Four peaks at 137.26 ppm,

45

131.18 ppm, 128.04 ppm and 124.31 pm indicated six aromatic carbons. At 123.30 ppm a

peak indicated a triazole carbon. At 59.88 ppm and 55.84 ppm two peaks represented the

three carbons in the methoxy groups. At 52.81 ppm and 37.20 ppm two peaks indicated

two aliphatic carbons.

O

ON3

OMe

OMe

MeO

HON

N

NO

O

OMe

OMeMeO

HO

CuSO4NaAscorbateEtOH

Equation 32

32 (58%)

Synthesis of ethyl 2-(4-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1H-1,2,3-triazol-1-

yl)acetate (32) (Equation 32). NMR results indicated that a mixture of 32 and 32 without

the hydroxyl group were formed. The product was not purified by column

chromatography.

46

3. Experimental

3.1 General procedures General procedure for click reactions

The click reactions were performed as outlined below. The individual data are given in

the description of the different syntheses. An azide was mixed with t-BuOH:H2O (1:1) in

a 20 mL screw-top scintillation vial. An alkyne and sodium ascorbate was added. The

mixture was stirred at room temperature until everything were dissolved. Finally copper

sulphate was added, and the mixture was allowed to stir at room temperature over night.

The reaction mixture was diluted with ice-water and a precipitate usually formed. The

precipitate was filtered off and washed 3 times with saturated ammonium chloride

solution and 2 times with cold diethyl ether. This was the standard procedure for isolation

of the product, unless another method is described for the individual experiments.

General procedure for one-pot click reactions

The one-pot click reactions were performed as outlined below. The individual data are

given in the description of the different syntheses. A bromide was mixed with t-

BuOH:H2O (1:1) in a 20 mL screw-top scintillation vial. Sodium azide, an alkyne and

sodium ascorbate was added. The mixture was stirred at room temperature until

everything were dissolved. Finally copper sulphate was added, and the mixture was

allowed to stir at room temperature over night. The reaction mixture was diluted with ice-

water and a precipitate usually formed. The precipitate was filtered off and washed 3

times with saturated ammonium chloride solution and 2 times with cold diethyl ether.

This was the standard procedure for isolation of the product, unless another method is

described for the individual experiments.

General procedure to prepare azides

The amounts of the different compounds and data for the individual reactions are given

below. The experiments were carried out at room temperature. Solvent (EtOH:H2O, 1:1)

was put in a round bottomed flask of a proper size, and the pH was measured. If the pH

47

was not around 7, some HCO3 (aq) or HCl was added. NaN3 was added to the solvent

while stirring. The bromide was added to the mixture while stirring. The mixture stirred

for 12 hours. EtOAc in equal volumes to the solvent was added to the mixture. The

mixture was washed with brine in equal volumes twice. The organic phase was dried

(MgSO4) and the organic solvent was evaporated under reduced pressure.

General procedure to prepare bromides

The amounts of the different compounds and data for the individual reactions are given

separately in the description for each experiment. The experiments were carried out at

under dry conditions at room temperature. The alcohol was weighed in a round bottomed

flask of suitable size and it was flushed with Argon. Dichloromethane was added to the

round bottomed flask via a syringe. Trietylamine was added via a syringe while stirring.

Bromoacetylchloride was added drop by drop via a syringe. The mixture was allowed to

stir over night. NaHCO3 (10%) was added until the bobbling stopped. The mixture was

washed with brine. The organic phase was dried (MgSO4) and the solvent was evaporated

under reduced pressure. Column chromatography was performed on the products.

48

3.2 Synthesis (3,4,5-Trimethoxy)methanol (1)

MeO

OMe

OMe

CH2OH

NaBH4 (0.76g, 20 mmol) was dissolved in EtOH:H2O (1:1, 20 mL) while stirring at 0ºC.

3,4,5-Trimethoxybenzaldehyde (7.85 g, 40mmol) was dissolved in THF:EtOH (1:3, 60

ml). The NaBH4 solution was added, in small portions, to the

3,4,5-trimethoxybenzaldehyde solution at 0ºC while stirring. After 5 min. the ice bath

was removed, and the mixture was stirred at room temperature for 2.5 hours. The reaction

was quenched with ice. The mixture was acidified to pH 1 with HCl (conc.), extracted

with EtOAc (3x100 mL), washed with brine (2x100 mL) and dried (MgSO4). The MgSO4

was filtered off and the solvent was evaporated under reduced pressure furnishing 8.03 g

(total yield 100%) as a slightly yellow colored oil. 1H NMR (CDCl3, 300 MHz) δ 6.58 (s,

2H), 4.62 (s, 2H), 3.85 (s, 6H), 3.82 (s, 3H), 2.03 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ

153.30, 137.23, 136.63, 103.75, 65.43, 60.80, 56.03.

5-(bromomethyl)-1,2,3-trimethoxybenzene (2)

MeO

OMe

OMe

CH2Br

49

The experiment was performed under dry conditions. (3,4,5-Trimethoxy)methanol

(0.99g, 5 mmol) was dissolved in dichloromethane (10 mL) while stirring. CBr4 (1.70g, 6

mmol) was added and dissolved. The mixture was put on an ice bath and the flask was

flushed with argon. Triphenylphosphin (1.71g, 6.5 mmol) was added in small portions.

The mixture was taken off the ice bath and was left to stir for over night at room

temperature. The mixture was washed with hexane (2x 20 mL) and CHCl3 (2x20 mL),

this caused precipitation. The mixture was filtered through silica 2x. The solvent was

evaporated under reduced pressure, furnishing 3.92g (total yield 58%) as white crystals.

Mp: 74-75oC; 1H NMR (CDCl3, 300 MHz) δ 6.58 (s, 2H), δ 4.62 (s, 2H), δ 3.85 (s, 6H), δ

3.82 (s, 3H), δ 2.03 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 153.30, 137.23, 136.63,

103.75, 65.43, 60.80, 56.03.

1,2,3-trimethoxy-5-(prop-2-ynyl)benzene (3)

OMe

OMeMeO

The experiment was performed under dry conditions. 5-(bromomethyl)-1,2-dimethoxy-3-

methylbenzene (0.66g, 2 mmol) and CuI (0.04g, 0.2 mmol) was weighed out in a flask.

The flask was flushed with N2. Dry THF (10 mL) was added and the mixture was stirred

until the solids dissolved. Ethynylmagnesium bromide in THF (0.5M, 8 mL) was added.

The mixture was stirred for 48 hours at 58oC. TLC showed that no product was formed.

The experiment was aborted.

1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (4)

50

OMe

OMeMeO

HO

The experiment was performed under dry conditions. 3,4,5-trimethoxybenzaldehyde

(1.96g, 10 mmol) and was weighed out in a flask. The flask was flushed with Argon. Dry

THF (20 mL) was added and the mixture was stirred until the solid dissolved. The

mixture was put on an ice bath. Ethynylmagnesium bromide in THF (0.5M, 24 mL) was

added. The mixture was stirred for 1 hour at 0oC. After 1 hour the ice bath was removed

and the mixture was stirred over night. TLC showed that product was formed. NH4Cl (20

mL) was added. The organic phase and the water phase were separated. The water phase

was extracted twice with diethyl ether and washed with brine. The organic phase was

collected and dried (MgSO4) and the solvent was evaporated under reduced pressure.

Flashcromatography was performed, furnishing 1.96g (total yield 88%) as white crystals;

Rf 0.42 (hexane:EtOAc, 1:1); 1H NMR (CDCl3, 300 MHz) δ 6.80 (s, 2H), 4.62 (s, 1H),

3.89 (s, 6H), 3.85 (s, 3H), 2.69 (d, J 2.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) δ 153.87,

138.10, 135.56, 103.64, 83.56, 74.89, 64.56, 60.84, 56.15.

5-ethynyl-1,2,3-trimethoxybenzene (5)

51

H3CO

OCH3

OCH3

The experiment was performed under dry conditions. A bath of acetone and dry ice was

prepared. A 250 mL round bottomed flask was flushed with Argon and put in the

acetone/dry ice bath. [(CH3)2CH]2NLi (1.8 M, 23.3 mL) measured out and transferred to

the round bottomed flask. C4H10N2Si (2.0 M, 18.8 mL) was carefully added. After 15

minutes, 3,4,5-trimethoxybenzaldehyde (5.89 g, 30 mmol) was weighed out and

dissolved in dry THF and added drop by drop to the mixture. The mixture was allowed to

stir over night at -78oC. The mixture was brought to room temperature. Brine (30 mL)

was added and the mixture was extracted with EtOAc (3 x 100 mL). The organic phase

was washed with brine (2 x 100 mL). The organic phase was collected and dried

(MgSO4) and the solvent was evaporated under reduced pressure. Column

chromatography was performed, furnishing 3.69 g (total yield 64%) as white crystals; mp

93-95oC; Rf 0.50 (Hexane:EtOAc 8:3); 1H NMR (CDCl3, 300 MHz) δ 6.73 (s, 2H), 3.85

(s, 9H), 3.03 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ 153.04, 139.30, 117.01, 109.36,

83.70, 76.19, 60.95, 56.15; HRMS calcd. for Chemical Formula: C11H12O3 [M+]:

192.0786, found: 192.0780.

Ethyl prop-2-ynylcarbamate (6)

NH

O

O

52

An ice bath was prepared. Propargylamine (0.54 g, 5 mmol) was dissolved in

dichloromethane (5 mL). Ethylchloroformate (0.27 g, 5 mmol) was dissolved in

dichloromethane (5 mL). The Propargylamine solution was added to the

Ethylchloroformate solution drop by drop while stirring at 0oC. The mixture was stirred

over night at room temperature. EtOAc (50 mL) was added. The mixture was washed

with NaHCO3 (20%, 2 x 50 mL). The organic phase was dried (MgSO4) and the solvent

was evaporated under reduced. NMR data indicated that only starting materials were

isolated.

N-(4-(N-prop-2-ynylsulfamoyl)phenyl)acetamide (7)

S

O

ONH

HN O

An ice bath prepared. Propargylamine (0.20 g, 2 mmol) was weighed in 25 mL round

bottomed flask. Pyridine (1 mL) was added, and the solution was stirred at 0oC. N-(4-(N-

prop-2-ynylsulfamoyl)phenyl)acetamide (0.43 g, 1.85 mmol) was added in small

portions. The mixture was stirred over night at room temperature. HCl (1M, 10 mL) and

EtOAc (20 mL) was added. The organic phase was washed with HCl (1 M, 10 x 10 mL).

The organic phase was dried (MgSO4) and the solvent was evaporated under reduced

pressure, furnishing 0.11 g (total yield 24%) as pink crystals; mp 192-193oC; Rf 0.40

(Hexane:EtOAc 1:5); 1H NMR (d-Aceton, 300MHz) δ= 9.49 (s, 1H), 7.84-7.77 (m, 4H),

3.81-3.79 (m, 2H), 2.12 (s, 3H), 2.09 (s, 1H); 13C NMR (d-Aceton, 75 MHz) δ 170.50,

145.15, 136.45, 130.08, 120.37, 80.73, 74.63, 34.13, 25.38; HRMS calcd. for

C11H12N2O3S [M+]: 252.0569 found: 252.0565.

N-(4-(N-prop-2-ynylsulfamoyl)phenyl)acetamide (7)

53

S

O

ONH

HN O

Large scale preparation of (7): an ice bath prepared. Propargylamine (2.48 g, 45 mmol)

was weighed in 250 mL round bottomed flask. Pyridine (40 mL) was added, and the

solution was stirred at 0oC. The round bottomed flask was flushed with Argon. N-(4-(N-

prop-2-ynylsulfamoyl)phenyl)acetamide (6.71g, 30 mmol) was added in small portions.

The mixture was stirred over night at room temperature. HCl (2 M, 70 mL) and EtOAc

(100 mL) was added. The organic phase was washed with HCl (2 M, 10 x 70 mL). The

resulting precipitate was filtered off, furnishing 3.25 g (total yield 43%) as pink crystals;

mp 192-193oC; Rf 0.40 (Hexane:EtOAc 1:5); 1H NMR (CDCl3, 300 MHz) δ 9.50 (s,

1H), 7.84-7.77 (m, 4H), 3.81-3.79 (m, 2H), 2.12 (s, 3H), 2.01 (s, 1H); 13C NMR

(CDCl3, 75 MHz) δ 170.50, 145.15, 136.45, 130.08, 120.37, 80.73, 74.63, 34.13, 25.38;

HRMS calcd. for C11H12N2O3S [M+]: 252.0569 found: 252.0565.

4-nitro-N-(prop-2-ynyl)benzenesulfonamide (8)

S

O

O

N+

O

O-

HN

An ice bath prepared. Propargylamine (1.69 g, 30 mmol) was weighed in 250 mL round

bottomed flask. Pyridine (30 mL) was added, and the solution was stirred at 0oC. The

round bottomed flask was flushed with Argon. 4-nitrobenzene-1-sulfonyl chloride (4.93

g, 20 mmol) was added in small portions. The mixture was stirred over night at room

temperature. HCl (2 M, 70 mL) and EtOAc (100 mL) was added. The organic phase was

washed with HCl (2 M, 10 x 70 mL). The mixture was brought to pH 7 with NaOH

54

(6M).The resulting precipitate was filtered off, furnishing 3.12 g (total yield 61%) as a

yellow solid; mp 152-154oC; Rf 0.33 (Hexane:EtOAc, 2:1); 1H NMR (DMSO, 200 MHz)

δ 8.54 (t, J 5.8 Hz, 1H), 8.45-8.38 (m, 2H), 8.09-8.04 (m, 2H), 3.79 (dd, J 2.6, 2H), 3.01

(t, J 2.6 Hz, 1H); 13C NMR (DMSO, 75 MHz) δ 149.53, 146.18, 128.34, 124.29, 78.72,

75.09, 31,81.

4-nitro-N-(prop-2-ynyl)benzenesulfonamide (8)

S

O

O

N+

O

O-

HN

Propargylamine (0.23 g, 4 mmol) was weighed in 100 mL round bottomed flask. 4-

nitrobenzene-1-sulfonyl chloride (0.99 g, 4 mmol) and water (20 mL) was added. The pH

of the mixture was adjusted to 8 with Na2CO3. The mixture was stirred at room

temperature and Na2CO3 was added to keep the pH at 8. After 2 hours the reaction was

stopped by adding HCl (12 M, 1 mL). The resulting precipitate was filtered off and

washed with water.

4-amino-N-(prop-2-ynyl)benzenesulfonamide (9)

S

O

ONH

NH2

N-(4-(N-prop-2-ynylsulfamoyl)phenyl)acetamide (1.51 g, 6 mmol) and NaOH (10 M, 60

mL) was refluxed 3 hours in a 250 mL round bottomed flask with a cooler. The mixture

was neutralized with HCl (3 M). NaOH (0.01 M) was added to make the mixture slightly

55

alkaline. The mixture was extracted with chloroform (3 x 100 mL), but the product did

not distribute in the organic phase. The water phase was evaporated under reduced

pressure and the resulting solid was dissolved in methanol. The solution was filtered

through a “plug” of MgSO4, celite and silica. Rf 0.38 (Hexane:EtOAc 1:4); 1H NMR (d6-

MeOH, 300 MHz); δ 7.53 (d, J 8.7 Hz, 2H), 6.69 (d, J 9.0 Hz, 2H), 3.65 (d, J 2.7 Hz,

2H), 2.47 (t, J 2.7 Hz, 1H), 2.16 (s, 1H); 13C NMR (d6-MeOH, 75 MHz) δ 154.28,

130.92, 127.12, 114.43, 79.93, 73.34, 33.18; HRMS calcd. for C9H10N2O2S [M+]:

210.0463, found: 210.0457.

Ethyl 2-azidoacetate (10) O

ON3

Ethyl 2-azidoacetate was prepared according to the general procedure for azides from

ethyl 2-bromoacetate (0.84 g, 5 mmol) and sodium azide (0.34 g, 5.25 mmol), furnishing

0.37 g (55%) as a colorless liquid. IR: 2109 cm-1, 1747 cm-1; 1H NMR (CDCl3, 300 MHz)

δ 4.24 (q, J 6.9 Hz, 2 H), 3.84 (s, 2H), 1.29 (d, J 6.9 Hz, 3H); 13C NMR (CDCl3, 75

MHz) δ 168.21, 61.79, 50.29, 14.05; HRMS calcd. for C4H7N3O2 [M+]: 129.0538, found:

129.0539.

(Azidomethyl)benzene (11) N3

(Azidomethyl)benzene was prepared according to the general procedure for azides from

benzyl bromide (3.42 g, 20 mmol) and sodium azide (1.37 g, 21 mmol), EtOH:H2O (1;1,

80 mL). The reaction yielded 2.28 g (86%) as a yellow liquid; Rf 0.80 (Hexane:EtOAc

56

2:1); 1H NMR (CDCl3, 300 MHz) δ 7.43-7.30 (m, 5 H), 4.35 (s, 2H); 13C NMR (CDCl3,

75 MHz) δ 135.35, 128.82, 128.29, 128.20, 54.80

1-(Azidomethyl)-4-nitrobenzene (12)

N+O O-

N3

1-(Azidomethyl)-4-nitrobenzene was prepared according to the general procedure for

azides from 4-nitrobenzyl bromide (3.42 g, 20 mmol) and sodium azide (1.37 g, 21

mmol), The reaction yielded 3.56 g (89%) as a yellow liquid; Rf 0.74 (Hexane:EtOAc

1:4); 1H NMR (CDCl3, 300 MHz) δ 8.26-8.19 (m, 2 H), 7.58-7.48 (m, 2H), 4.51 (s,2H); 13C NMR (CDCl3, 75 MHz) δ 144.74, 142.67, 129.89, 124.03, 53.72 ; HRMS calc for

C6H6N4O2: 178.0491, found: 178.0490.

4-(Azidomethyl)pyridine (13)

N

N3

The reaction was performed with dry conditions under Argon. 4-Pyridylcarbinol (0.22 g,

2 mmol) was weighed in a 25 mL round bottomed flask and diphenyl phosphorazide

(0.66 g, 2.4 mmol) was added via a syringe. Dry toluene (4 mL) was added via a syringe.

The mixture was put on an ice bath. DBU (0.37 g, 2.4 mmol) was added via a syringe.

The mixture stirred for 2 hours at 0oC, and then for another 20 hours at room temperature.

57

EtOAc (1 mL) was added and the mixture was extracted with toluene (3 x 7 mL), the

organic phase was evaporated under reduced pressure. A white crystalline powder was

obtained, but it was insoluble in all available deuterated solvents, hence no NMR results

were obtained. The experiment was aborted.

3-(Azidomethyl)pyridine (14)

N3

N

The reaction was performed with dry conditions under Argon. 3-Pyridylcarbinol (1.09 g,

10 mmol) was weighed in a 100 mL round bottomed flask and diphenyl phosphorazide

(3.30 g, 12 mmol) was added via a syringe. Dry toluene (18 mL) was added via a syringe.

The mixture was put on an ice bath. DBU (1.83 g, 12 mmol) was added via a syringe.

The mixture stirred for 4 hours at 0oC, and then for another 20 hours at room temperature.

The mixture was washed with water first, and then with HCl. This procedure resulted in 3

phases. The experiment was aborted.

3-(Bromomethyl)pyridine (15) N

Br

3-(Bromomethyl-)pyridine hydrobromide (0.52 g, 2 mmol) was weighed in a 25 mL

round bottomed flask and EtOH:H2O, 1:1 (4 mL) was added. The mixture was allowed to

stir at room temperature. NaOH (1 M) was added until the pH reached 8.The mixture

stirred over night. A white precipitate was observed, but extraction with EtOAc did not

succeed and the experiment was aborted.

2-Bromophenyl 2-bromoacetate (16)

58

O

BrOBr

The reaction was performed according to the general procedure for bromides. Chemicals

and amounts used: Bromoacetylchloride (1.73 g, 11 mmol), 2-bromphenol (1.73 g, 10

mmol), triethylamine (1.11 g, 11 mmol) and dichloromethane (20 mL). The reaction

furnished 0.87 g (30%) as a colorless liquid. Rf 0.60 (hexane:EtOAc, 3:1); 1H NMR

(CDCl3, 300 MHz) δ 7.62 (d, J 7.8 Hz, 1H) 7.35 (t, J 8.1 Hz, 1H) 7.18-7.13 (m, 2H) 4.37

(s, 2H) ; 13C NMR (CDCl3, 75 MHz) δ 164.96, 147.62, 133.44 ppm, 128.59, 127.85,

123.31, 115.71, 25.05.

Methyl 3-(4-(2-bromoacetoxy)phenyl)propanoate (17)

OBr

O

O

O

The reaction was performed according to the general procedure for bromides. Chemicals

and amounts used: Bromoacetylchloride (1.73 g, 11 mmol), methyl 3-(4-

hydroxyphenyl)propanoate (1.80 g, 10 mmol), triethylamine (1.11 g, 11 mmol) and

dichloromethane (20 mL). The reaction furnished 0.72 g (24%) as a white solid. Mp; 54-

55oC; Rf 0.38 (hexane:EtOAc, 3:1); 1H NMR (CDCl3, 300 MHz) δ 7.23 (d, J 8.7 Hz, 2H)

7.05 (d, J 8.7 Hz, 2H) 4.27 (s, 2H), 3.67 (s, 3H), 2.96 (t, J 8.1 Hz, 2H), 2.63 (t, J 7.8 Hz,

2H) ; 13C NMR (CDCl3, 75 MHz) δ 173.06, 165.91, 148.71, 138.71, 129.41, 121.07,

51.65, 40.85, 35.52, 30.25.

Ethyl 2-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)acetate (18)

59

MeO

MeO OMe

NN

NO

O

The reaction was performed as outlined in general procedure for one-pot click reactions.

The chemicals used and the data is described below.

Ethyl 2-bromoacetate (167 mg, 1 mmol), t-BuOH:H2O solution (1:1, 4 mL), sodium

azide (65 mg, 1.05 mmol), 5-ethynyl-1,2,3-trimethoxystilbene (192 mg, 1mmol), sodium

ascorbate (20 mg, 0.1 mmol) and copper sulphate (13 mg, 0.05 mmol). TLC showed that

the reaction was not completed. Sodium azide (38 mg, 0.5 mmol), sodium ascorbate (10

mg, 0.05 mmol) and copper sulphate (7 mg, 0.025 mmol) were added. The mixture was

allowed to stir over night. The reaction mixture was diluted with ice-water and EtOAc

(20 mL) was added. The organic phase was washed 3 times with saturated ammonium

chloride solution (10 mL). The organic phase was dried (MgSO4) and filtered. The

solvent was evaporated under reduced pressure, furnishing 165 mg (total yield 52%) as

slightly yellow colored crystals. Mp: 95-97oC; Rf 0.66 (Hexane:EtOAc, 1:10); 1H NMR

(CDCl3, 300MHz); δ 7.90 (s, 1H), 7.06 (s, 2H), 5.20 (s, 2H), 4.29 (q, J 7.8 Hz, 2H), 3.92

(s, 6H), 3.87 (s, 3H), 1.31 (t, J 7.8 Hz, 3H); 13C NMR (CDCl3, 300MHz); δ 166.27,

153.62, 138.24, 125.84, 120.77, 103.04, 62.50, 60.92, 56.24, 50.97, 14.06. A peak for the

second triazole carbon was not found in the spectrum. HRMS calc for C15H19N3O5:

321.1325, found; 321.1330.

Ethyl 2-(4-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1H-1,2,3-triazol-1-yl)acetate

(19)

60

OMeMeO

MeO

HO

NN

N

O

O



Ethyl 2-bromoacetate (668 mg, 4 mmol), t-BuOH:H2O solution (1:1,16 mL), sodium

azide (260 mg, 4.2 mmol), 1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (889 mg, 4mmol),

sodium ascorbate (79 mg, 0.4 mmol) and copper sulphate (50 mg, 0.2 mmol). The

mixture was diluted with ice water and washed with saturated ammonium chloride

solution (3 x 30 mL). The mixture was extracted with dichloromethane (2 x 50 mL), the

organic phase was dried (MgSO4) and evaporated under reduced pressure. NMR data

showed that only starting materials were isolated.

Diethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)malonate (20)

NN

N

O

O

O

O

61



Diethyl 2-bromomalonate (476 mg, 2 mmol), t-BuOH:H2O solution (1:1, 4 mL), sodium

azide (137 mg, 2.1 mmol), phenylacetylene (204 mg, 2 mmol), sodium ascorbate (40 mg,

0.2 mmol) and copper sulphate (25 mg, 0.1 mmol). The mixture was diluted with ice-

water and washed with saturated ammonium chloride solution (3 x 15 mL). The mixture

was extracted with EtOAc (3 x 20 mL).

The organic phase was dried (MgSO4) and filtered. The solvent was evaporated under

reduced pressure, a yellow liquid was obtained. NMR data showed that the product was

not pure.

Ethyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)propanoate (21)

N

N

N O

O



Ethyl-2-bromopropionate (362 mg, 2 mmol), t-BuOH:H2O solution (1:1, 4 mL), sodium




was extracted with EtOAc (3 x 20 mL). The organic phase was dried (MgSO4) and

filtered. The solvent was evaporated under reduced pressure, a green liquid was obtained.

NMR data showed that the product was not pure.

62

Ethyl 2-phenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (22)

N

NN

O

O



Ethyl bromphenylacetate (486 mg, 2 mmol), t-BuOH:H2O solution (1:1, 4 mL), sodium




was extracted with EtOAc (3 x 20 mL). The organic phase was dried (MgSO4) and

filtered. The solvent was evaporated under reduced pressure, a green liquid was obtained.

NMR data showed that the product was not pure.

2-Bromophenyl 2-(4-((4-acetamidophenylsulfonamido)methyl)-1H-1,2,3-triazol-1-

yl)acetate (23)

63

S

O

ONH

HN O

OBr

O

N

N N


The chemicals used and the data is described below. Chemicals: 2-Bromophenyl 2-

bromoacetate (294 mg, 1 mmol), t-BuOH:H2O solution (1:1, 2 mL), sodium azide (68

mg, 1.05 mmol), N-(4-(N-prop-2-ynylsulfamoyl)phenyl)acetamide (252 mg, 1 mmol),

sodium ascorbate (20 mg, 0.1 mmol) and copper sulphate (12 mg, 0.05 mmol). The

mixture was diluted with ice-water and washed with saturated ammonium chloride

solution (3 x 10 mL). The mixture was extracted with EtOAc (3 x 15 mL). The organic

phase was dried (MgSO4) and filtered. NMR data showed that no product was isolated.

2-Bromophenyl 2-(4-phenyl-1H-1,2,3-triazol-1-yl)acetate (24)

O

BrO

N

N

N


The chemicals used and the data is described below. Chemicals: 2-Bromophenyl 2-


64

mg, 1.05 mmol), phenylacetylene (102 mg, 1 mmol), sodium ascorbate (20 mg, 0.1

mmol) and copper sulphate (12 mg, 0.05 mmol). The mixture was diluted with ice-water

and washed with saturated ammonium chloride solution (3 x 10 mL). The mixture was

extracted with EtOAc (3 x 15 mL). TLC showed that no product was formed, and the

experiment was aborted.

Ethyl 2-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)acetate (25)

O2N

O O

N

N

N


The chemicals used and the data is described below. Ethyl bromoacetate (332 mg, 2

mmol), t-BuOH:H2O solution (1:1, 4 mL), sodium azide (137 mg, 2.1 mmol), 1-ethynyl-

4-nitrobenzene (97%, 303 mg, 2 mmol), sodium ascorbate (40 mg, 0.2 mmol) and copper

sulphate (25 mg, 0.1 mmol). Total yield 292 mg (53%); mp 144-145oC; Rf 0.66

(Hexane:EtOAc 1:4); 1H NMR (DMSO, 300 MHz) δ 8.85 (s, 1H), 8.32 (d, J 9.0 Hz,

2H), 8.14 (d, J 9.0 Hz, 2H), 5.52 (s, 2H), 4.21 (q, J 7.2 Hz, 2H), 1.24 (t, J 7.2 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 166.98, 146.59, 144.38, 136.79, 128.33, 125.94, 124.23,

61.58, 50.63, 13.89.

Ethyl 2-(4-(3-fluorophenyl)-1H-1,2,3-triazol-1-yl)acetate (26)

65

O O

N

N

N

F



Ethyl bromoacetate (332 mg, 2 mmol), t-BuOH:H2O solution (1:1, 4 mL), sodium azide

(137 mg, 2.1 mmol), 1-ethynyl-3-fluorobenzene (98%, 245 mg, 2 mmol), sodium

ascorbate (40 mg, 0.2 mmol) and copper sulphate (25 mg, 0.1 mmol). Total yield 209 mg

(42%) as a slightly green solid; Mp: over 250oC; Rf 0.72 (hexane:EtOAc, 1:4); 1H NMR

(DMSO, 300 MHz) δ 8.68 (s, 1H), 7.72-7.14 (m, 4H), 5.47 (s, 2H), 4.20 (q, J 7.2 Hz,

2H), 1.04 (t, J 7.2 Hz, 3H); HRMS calcd. for: C12H12FN3O2 [M+]: 249.0914, found:

249.0913.

Ethyl 2-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)acetate (25)

O2N

O O

N

N

N

The reaction was performed as outlined in general procedure for one-pot click reactions,

at a temperature of 40oC. The chemicals used and the data is described below. Ethyl

66


mg, 4.2 mmol), 1-ethynyl-4-nitrobenzene (97%, 606 mg, 4 mmol), sodium ascorbate (80

mg, 0.4 mmol) and copper sulphate (50 mg, 0.2 mmol). Total yield 961 mg (87%); mp

144-145oC; Rf 0.66 (Hexane:EtOAc 1:4); 1H NMR (DMSO, 300 MHz) δ 8.85 (s, 1H),

8.32 (d, J 9.0 Hz, 2H), 8.14 (d, J 9.0 Hz, 2H), 5.52 (s, 2H), 4.21 (q, J 7.2 Hz, 2H), 1.24

(t, J 7.2 Hz, 3H); 13C NMR (DMSO, 75 MHz) δ 166.98, 146.59, 144.38, 136.79, 128.33,

125.94, 124.23, 61.58, 50.63, 13.89..

Ethyl 2-(4-((4-acetamidophenylsulfonamido)methyl)-1H-pyrazol-1-yl)acetate (28)

S

O

ONH

HN

O

NN

NO

O



Ethyl bromoacetate (166 mg, 1 mmol), t-BuOH:H2O solution (1:1, 4 mL), sodium azide

(68 mg, 1.05 mmol), N-(4-(N-prop-2-ynylsulfamoyl)phenyl)acetamide (252 mg, 1

mmol), sodium ascorbate (20 mg, 0.1 mmol) and copper sulphate (13 mg, 0.05 mmol).

Total yield 221 mg (88%); mp 176-178oC; 1H NMR (DMSO, 300 MHz) δ 10.31 (s, 1H),

8.03 (s, 1H), 7.92 (s, 1H), 7.80-7.65 (m, 4H), 5.32 (s, 2H), 4.17 (q, J 7.1 Hz, 2H), 4.03 (s,

2H), 2.09 (s, 3H), 1.22 (t, J 7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 168.87, 167.07,

142.67, 133.82, 127.64, 124.61, 118.48, 61.35, 50.17, 38.60, 24.04, 13.88; HRMS calcd.

for C15H19N5O5S [M+]: 381.1107, found: 381.1074.

67

N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)-4-nitrobenzenesulfonamide (29)

S

O

O

N+

O

O-

HN

NN

N

The reaction was performed as outlined in general procedure for click reactions. The

chemicals used and the data is described below.

(Azidomethyl)benzene (266 mg, 2 mmol), t-BuOH:H2O solution (1:1, 4 mL), 4-nitro-N-

(prop-2-ynyl)benzenesulfonamide (509 mg, 2 mmol), sodium ascorbate (40 mg, 0.2

mmol) and copper sulphate (25 mg, 0.1 mmol). A total yield 572 mg (77%) as a yellow

solid. Rf 0.56 (hexane:EtOAc (1:4); mp 157-158oC; 1H NMR (DMSO, 300 MHz) δ 8.53

(s, 1H), 8.31 (d, J 9.0 Hz, 2H), 7.97 (d, J 9.0 Hz, 2H), 7.90 (s, 1H), 7.35-7.22 (m, 5H),

5.49 (s, 2H), 4.14 (s, 2H); 13C NMR (DMSO, 75 MHz) δ 149.32, 146.10, 135.80, 128.58,

128.06, 127.99, 127.83, 124.29,123.34, 52.59, 37.83.

1-(1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)-N-((4-

nitrophenylsulfonyl)methyl)methanamine (30)

S

O

O

N+

O

O-NH

NN

N

O2N

68


chemicals used and the data is described below. Chemicals: 1-(Azidomethyl)-4-

nitrobenzene 356 mg, 2 mmol), t-BuOH:H2O solution (1:1, 4 mL), 4-nitro-N-(prop-2-

ynyl)benzenesulfonamide (509 mg, 2 mmol), sodium ascorbate (40 mg, 0.2 mmol) and

copper sulphate (25 mg, 0.1 mmol). The reaction provided a poor yield and TLC showed

that the product was impure.

1-(1-(4-Nitrobenzyl)-1H-1,2,3-triazol-4-yl)-N-((4-

nitrophenylsulfonyl)methyl)methanamine (30)

S

O

O

N+

O

O-NH

NN

N

O2N


chemicals used and the data is described below. Chemicals: 1-(Azidomethyl)-4-

nitrobenzene 356 mg, 2 mmol), t-BuOH:H2O solution (1:1, 8 mL), 4-nitro-N-(prop-2-

ynyl)benzenesulfonamide (509 mg, 2 mmol), sodium ascorbate (40 mg, 0.2 mmol) and

copper sulphate (25 mg, 0.1 mmol). A total yield 572 mg (77%) as a yellow solid. Rf

0.36 (hexane:EtOAc, 1:4); mp 183-185oC; 1H NMR (DMSO, 300 MHz) δ 8.58 (s, 1H),

8.31 (d, J 8.7 Hz, 2H), 8.22 (d, J 9.0 Hz, 2H), 7.99 (d, J 8.4 Hz, 3H), 7.47 (d, J 8.7 Hz,

2H), 5.69 (s, 2H), 4.17 (s, 2H); 13C NMR (DMSO, 75 MHz) δ 149.26, 147.11, 146.08,

143.15, 128.88, 127.97, 124.26, 123.70, 58.91, 37.82.

4-Nitro-N-((1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-4-

yl)methyl)benzenesulfonamide (31)

69

S

O

O

N+

O

O-

NH

NN

N

OMe

MeO

MeO

H2O (20 mL), 4-nitrobenzene-1-sulfonyl chloride (492 mg, 2 mmol) and propargylamine

(112 mg, 2 mmol) was mixed in 250 mL round bottomed flask. The pH was set to 8 with

Na2CO3. 5-(Azidomethyl)-1,2,3-trimethoxybenzene (442 mg, 2 mmol), sodium ascorbate

(40 mg, 0.2 mmol), EtOH (20 mL) and copper sulphate (25 mg, 0.1 mmol) was added.

The mixture was allowed to stir over night. Ice water was added and a precipitate formed.

The precipitate was filtered off and washed with ammonium solution (5%, 3 x 25 mL)

and cold diethyl ether (3 x 25 mL), furnishing a white solid total yield 400 mg (43%). Rf;

0.32 (hexane:EtOAc, 1:4); mp 148-152oC; 1H NMR (DMSO, 300 MHz) δ 8.5 (s, 1H),

8.34 (d, J 9.0 Hz, 2H), 8.00 (d, J 9.0 Hz, 3H), 6.67 (s, 2H), 5.41 (s, 2H), 4.12 (s, 2H),

3.75 (s, 6H), 3.63 (s,3H); 13C NMR (DMSO, 75 MHz) δ 152.90, 149.39, 145.95, 143.20,

137.26, 131.18, 128.04, 124.31, 123.30, 59.88, 55.84, 52.81, 37.20;

Ethyl 2-(4-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1H-1,2,3-triazol-1-yl)acetate

(32)

70

OMe

OMe

MeO

HON

N

NO

O


chemicals used and the data is described below. Ethyl 2-azidoacetate (259 mg, 2 mmol),

t-BuOH:H2O solution (1:1, 8 mL), 1-(3,4,5-trimethoxyphenyl)prop-2-yn-1-ol (445 mg, 2

mmol), sodium ascorbate (40 mg, 0.2 mmol) and copper sulphate (25 mg, 0.1 mmol).

71

4 Further studies and conclusion

4.1 Further studies In order to obtain antibacterial activity for the prepared sulfonamides 28, 29, 30 and 31,

hydrolysis of the amide group or reduction of the nitro group needs to be done. Due to

time limits, these two reactions were not performed. This chemistry should be possible to

do with established methods. In preliminary studies, hydrolysis of sulfonamide 9 in basic

aqueous conditions afforded the desired sulfonamide product. However, this sulfonamide

was difficult to obtain without sodium chloride as a contaminant, and further studies

should be done in order to obtain libraries of pure sulfonamides.

This one-pot methodology was employed for a wide range of substituted terminal alkynes

in our group as depicted in Scheme 1.32

OBr

O NaN3 (1.0 eqv)R1

CuSO4 (5%)NaAscorbate (10%)t-BuOH/H2O (1:1)

ON

O NNR1

ON

O NN

ON

O NN

O

ON

O NN

ONO2

OMe

ON

O NN

N ON

ON N

SO2

OO

1 (91%) 2 (89%)

4 (81%)

3 (89%)

6 (85%)5 (88 %)

ON

O NN

NO2

7 (80 %)

ON

O NN

8 (94 %)

ON

O NN

9 (88 %)

OMe

OMe

OMe

O NO NN NH

O

SO

OHN

O N

O NN NO2SO

OHN

Br

Scheme 1

72

4.2 Conclusion

A one-pot procedure for the direct conversion of α-halo esters to 1,2,3-triazoles has been

developed. These reactions were efficiently performed in neutral aqueous solutions (pH=

7-8) at ambient temperature. Molar equivalents of the halide, sodium azide and alkyne

are employed in this mild 1,3-dipolar cycloaddition reaction. The method circumvents the

problems encountered with the isolation of organic azides, and complements other

recently published methods for the preparation of 1,2,3-triazoles.33-35 The operational

simplicity of this method makes it attractive for preparative applications as well as for the

synthesis of screening libraries for drug discovery.

This method should be useful for preparation of libraries of biologically active

compounds, for example for sulfonamides such as 7, 8 and 9. Furthermore, the

advantages of the guiding principles of click chemistry, as exemplified for the Cu(I)-

catalyzed cycloaddition between azides and terminal alkynes, has been used for the

preparation of several new 1,4-disubstituted 1,2,3-triazoles.

73

5. References 1. Ng, R. Drugs-From Discovery to Approval (Wiley-Liss, 2004). 2. Gordon, E. M. & James F. Kerwin, J. Combinatorial Chemistry and Molecular

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